Discovery and Characterization of Small Molecule Inhibitors of the BET Family Bromodomains

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• 作者：Chun-wa Chung ; Herv茅 Coste ; Julia H. White ; Olivier Mirguet ; Jonathan Wilde ; Romain L. Gosmini ; Chris Delves ; Sylvie M. Magny ; Robert Woodward ; Stephen A. Hughes ; Eric V. Boursier ; Helen Flynn ; Anne M. Bouillot ; Paul Bamborough ; Jean-Marie G. Brusq ; Fran莽oise J. Gellibert ; Emma J. Jones ; Alizon M. Riou ; Paul Homes ; Sandrine L. Martin ; Iain J. Uings ; J茅r么me Toum ; Catherine A. Cl茅ment ; Anne-B茅n茅dicte Boullay ; Rachel L. Grimley ; Florence M. Blandel ; Rab K. Prinjha ; Kevin Lee ; Jorge Kirilovsky ; Edwige Nicodeme
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：June 9, 2011
• 年：2011
• 卷：54
• 期：11
• 页码：3827-3838
• 全文大小：1292K
• 年卷期：v.54,no.11(June 9, 2011)
• ISSN：1520-4804

文摘

Epigenetic mechanisms of gene regulation have a profound role in normal development and disease processes. An integral part of this mechanism occurs through lysine acetylation of histone tails which are recognized by bromodomains. While the biological and structural characterization of many bromodomain containing proteins has advanced considerably, the therapeutic tractability of this protein family is only now becoming understood. This paper describes the discovery and molecular characterization of potent (nM) small molecule inhibitors that disrupt the function of the BET family of bromodomains (Brd2, Brd3, and Brd4). By using a combination of phenotypic screening, chemoproteomics, and biophysical studies, we have discovered that the protein鈥損rotein interactions between bromodomains and acetylated histones can be antagonized by selective small molecules that bind at the acetylated lysine recognition pocket. X-ray crystal structures of compounds bound into bromodomains of Brd2 and Brd4 elucidate the molecular interactions of binding and explain the precisely defined stereochemistry required for activity.